Arrhythmias remain a major cause of morbidity and mortality. Brugada syndrome is a rare, autosomal dominant, male predominant form of idiopathic ventricular fibrillation characterized by a right bundle branch block pattern and ST elevation in the right precordial leads of the surface EKG. The only effective treatment is an implantable cardioverter-defibrillator. Mutations of the cardiac Na+ channel SCN5A cause some cases of Brugada syndrome. Most SCN5A mutations decrease inward Na+ current, and Na+ channel blockers enhance the EKG phenotype. Mutations in other genes have not been reported, and it isn't clear whether the malignancy of arrhythmias and/or the efficacy of drug testing depend on the gene defect. The reason for male predominance is also unknown. During the initial period of this project, we identified a large multigenerational family with Brugada syndrome characterized by progressive conduction disease, age- and sex-dependent penetrance, minimal response to the Na+ channel blocker procainamide, and a low frequency of ventricular arrhythmias or sudden death. Linkage was present to an approximately4 cM region on chromosome 3p22-24 (max LOD score = 4.0) and SCN5A was excluded (LOD score < -2). More recently, we identified two other large families and several small families with Brugada syndrome or arrhythmogenic right ventricular dysplasia (ARVD). Two of the small families have mutations in SCN5A, while one of the large Brugada families does not link to SCN5A or to the new chromosome 3 locus. In this competing renewal, we will test the hypothesis that Brugada syndrome results from mutations in genes other than SCN5A that decrease the cardiac Na+ current in a gender-dependent manner, through the use of refined phenotyping, fine mapping, and candidate gene approaches. We will 1) clone the gene on chromosome 3p22-24 that causes the Brugada syndrome; 2) identify novel loci, genes, and mutations responsible for Brugada syndrome and ARVD in other families, and 3) probe the molecular basis of the gender differences in disease penetrance using a rabbit model.